P1379: OPTIMIZATION OF FLUDARABINE PHARMACOKINCETICS TO REDUCE THE RELAPSE INCIDENCE IN AML PATIENTS AFTER ALLOGENEIC STEM CELL TRANSPLANTATION
Authors: T. Thavayogarajah, G. Nair, S. Balabanov, M. G. Manz, D. Müller, U. Schanz
Journal: HemaSphere (2022)

Background: Acute myeloid leukemia (AML) is a hematological, clonal malignancy of the myeloid stem cell precursors, which is proliferative and is characterized by clonal evolution and genetic heterogeneity. For adverse risk acute myeloid leukemias, allogeneic stem cell transplantation (allo HCT) is one of the most potent curative options. Unfortunately, disease relapse is still around 40% in the first year after HSCT. In allo HCT, fludarabine is a frequently used agent, mainly in reduced intensity conditioning regimes. It is often combined with busulfan for which dose individualization based on pharmacokinetics with area under the curve (AUC) determination is used successfully for many years. It has already been shown that fludarabine exposure might be predictive for the survival in allo HCT and it is suggested that individualized dosing can improve the survival after transplantation within the first year. Actually for fludarabine dose calculation in adults, only the body surface area is used, which might either result in too high exposition causing increased toxicity or with too low exposure and increased relapse incidence (RI). With the aim to reduce RI we established pharmacokinetic measurements for fludarabine in addition and combined to the established ones for busulfan. Aims: Definition of the pharmacokinetic target for optimal fludarabine exposure during conditioning prior to HCT and establishment of a pharmacokinetic population model to support target attainment in individual patients. Methods: Fludarabine was measured with a validated LC-MS/MS method. The exposure, expressed as AUC, was calculated for each patient using a three-compartmental model (adapted from Langenhorst et al.) in n=19 consecutive patients receiving a conditioning regime with fludarabine being diagnosed with acute myeloid leukemia. Fludarabine was given on days -7 to -2 with a dose calculation based on 30mg/m2 infused over 30 minutes. In addition patients received peroral busulfan 4mg/kg bw on days -3 and -2 and ATG 10mg/kg bw (Grafalon®) on days -4 to -1. Results: So far, there is no dose individualization based on pharmacokinetic parameters for fludarabine specifically suggested in AML patients. The study published by Langenhorst et al. mixed up benign and malignant hematological malignancies, suggests lower optimal fludarabine AUC than we observed in our patients. We have seen that the fludarabine AUC were higher within our patients. In the analysis of Langenhorst et al. the optimal AUC was postulated to be 20 mg*h/l. In our (n=19) AML patients the median of the AUC was 42.97 (+/- 11.5) mg*h/l, twice as high than the suggested level for an optimal toxicity profile. However, none of our patients experienced any acute toxicity (within 30 days after transplant). Our 1 year TRM is stable for many years with 2-4%. Moreover, there was also no major toxicity (e.g. cytopenias, infections) seen at day 100. So far, we did not see a low retrospective RI (currently 35% at 1 year) despite the AUC was much higher than the suggested optimal levels. Summary/Conclusion: In a regimen with more (6 vs 4), but lower single fludarabine dosage (30mg/m2 vs 40mg/m2) and a shorter infusion duration (30min vs 60min) resulting in higher AUC (40mg*h/l vs 20 mg*h/l) than previously published. Within our small cohort, a low RI or high TRM seem not to be observed compared with a retrospective cohort. Further prospective data within an observational study are needed.